Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3

Definitions

• This invention relates to novel keto intermediates, their preparation and their use in preparing other compounds.
• a group of octahydropyrazolo[3,4-g]quinolines is disclosed in United States Patent 4,198,415 issued April 15, 1980, and in a divisional application thereof, United States Patent 4,230,861 issued October 28, 1980. Both intermediates and final products are disclosed therein and one reaction sequence so described is as follows: wherein R is H, C 1 -C 3 alkyl, allyl or benzyl, R 1 is H or COOZ' and Z ⁇ is C 1 -C 2 alkyl, benzyl, a-methylbenzyl, or phenylethyl.
• the compounds of formula IIIa or IIIb where R 1 is H and R is C 1 -C 3 alkyl or allyl are useful as inhibitors of prolactin secretion and in the treatment of Parkinson's syndrome.
• the compounds of formula IIIa or IIIb where R and R 1 are H, where R is benzyl or where R 1 is COOZ' are intermediates.
• the intermediates are converted by methods disclosed in the above patents to drugs.
• the reagent used to transform the 1-substituted-3-permissibly substituted-6- oxodecahydroquinoline (I) to the intermediate (II) is a dimethylformamide acetal such as dimethylformamide dimethylacetal.
• a trans-dl-1-substituted-3--permissibly-substituted-6-oxodeca- hydroquinoline (I) is formvlated with a C l -C 6 alkyl formate in the presence of base to yield a trans-dl-1-substituted-3-permissibly-substituted-6-oxo-7- formyldecahydroquinoline, represented as a series of tautomeric structures (IVa-d).
• This intermediate is ordinarily not isolated and characterized as such but is reacted immediately in situ with hydrazine to yield as a mixture of tautomers--trans-dl-5-substituted-7- permissibly-substituted-4,4a,5,6,7,8,8a,9-octahydro- lH-pyrazolo[3,4-g]quinoline (IIIa) and trans-dl-5- substituted-7-permissibly-substituted-4,4a,5,6,7,8,8a,9- octahydro-2H-pyrazolo[3,4-g]quinoline (IIIb).
• the first step of the above reaction is a modification of a Claissen condensation wherein a methylene group activated by an adjacent carbonyl group can be acylated in the presence of base.
• the base commonly employed is sodium ethylate.
• other bases such as the alkali metal t-alkoxides and hydrides, specifically, potassium t-butoxide, potassium t-amylalkoxide, or sodium hydride, can also be used.
• the Claissen condensation reaction (I ⁇ IV) is also usually carried out in ethanolic solution.
• other lower alkanols and similar polar anhydrous solvents can be employed as reaction media.
• Suitable solvents are tetrahydrofuran (THF), diethyl ether, dimethoxyethane, dioxane, dimethylsulfoxide (DMSO), dimethylformamide (DMF) and t-butanol.
• THF tetrahydrofuran
• diethyl ether dimethoxyethane
• dioxane dimethylsulfoxide
• DMSO dimethylsulfoxide
• DMF dimethylformamide
• t-butanol tetrahydrofuran
• Tetrahydrofuran is preferred as the solvent for the entire process in Reaction Scheme I.
• temperature of the reaction is not critical, a range from about -20°C. to reflux may be used, with 0°C. to room temperature being preferred.
• hydrazine is specified but hydrazine hydrate or salts of hydrazine can be used with equal success.
• Suitable solvents for the ring closure step are water, C i -C 4 alkanols, especially t-butanol, THF, DMSO, dimethoxyethane, dioxane, and diethyl ether.
• the C reaction can be run at a temperature from about 0°C. to reflux, with room temperature being preferred.
• both steps of the procedure can be carried out in the same reactor; i.e., it can be a "one-pot" process.
• water or a C 1 -C 4 alkanol can be added to the solvent system.
• a range of pH from about 13 to about 0 can be used, with a pH of about 9 being preferred.
• the preferred pH of about 9 is obtained by adding 10% HC1 solution (1 mole) to the reaction mixture.
• a temperature range from about 0°C. to reflux can be used, room temperature is preferred.
• a second advantage is that the yields of the pyrazole tautomers (IlIa + IIIb) are superior to those encountered with the process of the prior art which uses dimethylformamide dimethylacetal as a reagent.
• a further advantage is that the preferred formylating chemical employed, ethyl formate, is relatively inexpensive compared to dimethylformamide dimethylacetal.
• the numbering of the ketone starting material (I) is different from that of the pyrazole final product (III).
• the asymmetric bridgehead carbon adjacent to the quinoline nitrogen is numbered 8a in the ketone while it is numbered 4a in the pyrazole.
• the other asymmetric bridgehead carbon is numbered 4a in the ketone while it is numbered 8a in the final product.
• the racemic pairs of formulae IIIa and IIIb are ordinarily referred to as a cis-dl pair and a trans-dl pair.
• the configuration of the molecule at C-4a and C-8a in the cis-dl pair would be a 4aR,8aS, and 4aS,8aR and for the trans-dl pair, 4aR,8aR, and 4aS,8aS.
• the starting chemical configurations are of course maintained in the synthesis of the pyrazoloquinoline since the Claissen condensation and subsequent ring closure with hydrazine do not affect configuration at these optical centers.
• An advantage of the process set forth in Reaction Scheme II lies in the fact that the trans-dl-ketone (I) is resolved and the pure 4aR,8aR stereoisomer (Ia) cyclized to yield an optically-active trans-4aR,8aR-octahydropyrazolo[3,4-g]quinoline, rather than cyclizing the trans-dl - racemate and resolving the trans-dl-pyrazoloquinoline. Since one-half at least of a racemic mixture is discarded during a resolution, it is clearly more economical to discard half of a starting material than half of a final product, particularly since organic reactions such as the cyclization of the ketoquinoline to a pyrazoloquinoline are never quantitative.
• reaction mixture was stirred for 30 minutes at ambient temperature at which time tlc indicated that no ketone starting material was present.
• the reaction mixture was then poured into dilute (10%) aqueous sodium hydroxide and the alkaline mixture extracted with methylene dichloride (equal volume). The extract was dried and the solvent removed by evaporation in vacuo to yield 1.31 g. of a yellow oil comprising crude trans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and 2H)pyrazolo[3,4-g]quinoline.
• This oil was converted to the dihydrochloride salt which melted at about 252-263°C. after recrystallization from a methanol/acetone solvent mixture.
• the above 7-formyl product can be further reacted to prepare the compounds of formula IIIa and IIIb by methods disclosed above.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• General Health & Medical Sciences (AREA)
• Neurology (AREA)
• Veterinary Medicine (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Quinoline Compounds (AREA)
• Steroid Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Extraction Or Liquid Replacement (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Crystals, And After-Treatments Of Crystals (AREA)

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• 1983
  • 1983-07-26 ES ES524453A patent/ES524453A0/es active Granted
  • 1983-07-27 PT PT77111A patent/PT77111B/pt unknown
  • 1983-07-27 PL PL24320083A patent/PL243200A1/xx unknown
  • 1983-07-27 EP EP83304340A patent/EP0110496B1/de not_active Expired
  • 1983-07-27 ZA ZA835501A patent/ZA835501B/xx unknown
  • 1983-07-27 CA CA000433331A patent/CA1259313A/en not_active Expired
  • 1983-07-27 HU HU86814A patent/HU194176B/hu unknown
  • 1983-07-27 DK DK343283A patent/DK343283A/da unknown
  • 1983-07-27 IL IL69358A patent/IL69358A/xx not_active IP Right Cessation
  • 1983-07-27 RO RO111743A patent/RO86894B/ro unknown
  • 1983-07-27 JP JP58138681A patent/JPS5982366A/ja active Granted
  • 1983-07-27 DE DE8383304340T patent/DE3373303D1/de not_active Expired
  • 1983-07-27 KR KR1019830003503A patent/KR870000234B1/ko not_active IP Right Cessation
  • 1983-07-27 AT AT83304340T patent/ATE29252T1/de not_active IP Right Cessation
  • 1983-07-27 GB GB08320248A patent/GB2130576B/en not_active Expired
  • 1983-07-27 DD DD83253428A patent/DD210047A5/de unknown
  • 1983-07-27 AU AU17339/83A patent/AU551687B2/en not_active Ceased
  • 1983-07-27 PL PL25013783A patent/PL250137A1/xx unknown
  • 1983-07-27 GR GR72055A patent/GR77559B/el unknown
  • 1983-07-27 HU HU832646A patent/HU190728B/hu not_active IP Right Cessation
  • 1983-07-27 IE IE1773/83A patent/IE55668B1/en not_active IP Right Cessation
  • 1983-07-27 NZ NZ205031A patent/NZ205031A/en unknown
  • 1983-07-27 FI FI832719A patent/FI832719A/fi not_active Application Discontinuation
• 1991
  • 1991-03-27 JP JP3089660A patent/JPH04217979A/ja active Granted
  • 1991-03-27 JP JP3089661A patent/JPH0662618B2/ja not_active Expired - Lifetime

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